Haploinsufficiency for p190B RhoGAP Inhibits MMTV-Neu Tumor Progression

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Haploinsufficiency for p190B RhoGAP Inhibits MMTV-Neu Tumor Progression

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dc.contributor.author Heckman-Stoddard, Brandy M
dc.contributor.author Vargo-Gogola, Tracy
dc.contributor.author McHenry, Peter R
dc.contributor.author Jiang, Vivian
dc.contributor.author Herrick, Matthew P
dc.contributor.author Hilsenbeck, Susan G
dc.contributor.author Settleman, Jeffrey Evan
dc.contributor.author Rosen, Jeffrey M.
dc.date.accessioned 2011-11-22T16:29:58Z
dc.date.issued 2009
dc.identifier.citation Heckman-Stoddard, Brandy M., Tracy Vargo-Gogola, Peter R. McHenry, Vivian Jiang, Matthew P. Herrick, Susan G. Hilsenbeck, Jeffrey Settleman, and Jeffrey M. Rosen. 2009. Haploinsufficiency for p190B RhoGAP inhibits MMTV-Neu tumor progression. Breast Cancer Research 11(4): R61. en_US
dc.identifier.issn 1465-5411 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:5350704
dc.description.abstract Introduction: Rho signaling regulates key cellular processes including proliferation, survival, and migration, and it has been implicated in the development of many types of cancer including breast cancer. P190B Rho GTPase activating protein (RhoGAP) functions as a major inhibitor of the Rho GTPases. P190B is required for mammary gland morphogenesis, and overexpression of p190B in the mammary gland induces hyperplastic lesions. Hence, we hypothesized that p190B may play a pivotal role in mammary tumorigenesis. Methods: To investigate the effects of loss of p190B function on mammary tumor progression, p190B heterozygous mice were crossed with an MMTV-Neu breast cancer model. Effects of p190B deficiency on tumor latency, multiplicity, growth, preneoplastic progression and metastasis were evaluated. To investigate potential differences in tumor angiogenesis between the two groups, immunohistochemistry to detect von Willebrand factor was performed and quantified. To examine gene expression of potential mediators of the angiogenic switch, an angiogenesis PCR array was utilized and results were confirmed using immunohistochemistry. Finally, reciprocal transplantation of tumor fragments was performed to determine the impact of stromal deficiency of p190B on tumor angiogenesis. Results: P190B deficiency reduced tumor penetrance (53% of \(p190B^{+/-}Neu\) mice vs. 100% of \(p190B^{+/+}Neu\) mice formed tumors) and markedly delayed tumor onset by an average of 46 weeks. Tumor multiplicity was also decreased, but an increase in the number of preneoplastic lesions was detected indicating that p190B deficiency inhibited preneoplastic progression. Angiogenesis was decreased in the p190B heterozygous tumors, and expression of a potent angiogenic inhibitor, thrombospondin-1, was elevated in \(p190B^{+/-}Neu\) mammary glands. Transplantation of \(p190B^{+/-}Neu\) tumor fragments into wild-type recipients restored tumor angiogenesis. Strikingly, \(p190B^{+/+}Neu\) tumor fragments were unable to grow when transplanted into \(p190B^{+/-}Neu\) recipients. Conclusions: These data suggest that p190B haploinsufficiency in the epithelium inhibits MMTV-Neu tumor initiation. Furthermore, p190B deficiency in the vasculature is responsible, in part, for the inhibition of MMTV-Neu tumor progression. en_US
dc.language.iso en_US en_US
dc.publisher BioMed Central en_US
dc.relation.isversionof doi:10.1186/bcr2352 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750123/pdf/ en_US
dash.license LAA
dc.title Haploinsufficiency for p190B RhoGAP Inhibits MMTV-Neu Tumor Progression en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Breast Cancer Research en_US
dash.depositing.author Settleman, Jeffrey Evan
dc.date.available 2011-11-22T16:29:58Z
dash.affiliation.other HMS^Medicine-Massachusetts General Hospital en_US

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